TAXOL.RTM. (paclitaxel) was first isolated from the stem bark of Western Yew, Taxus brevifolia Nut. (Taxaceae) and has the following structure (with the (C)2'-, 6-, 7-, and 13th-positions indicated): ##STR2## It was recently approved for the treatment of ovarian cancer; and studies involving breast, colon, and lung cancers have shown promising results.
Paclitaxel is unique among antimitotic drugs in that it promotes the assembly of stable microtubules from tubulin even under otherwise unfavorable conditions. The drug binds to microtubules, stabilizing them from depolymerization, thus disrupting the tubulin-microtubule equilibrium and consequently inhibiting mitosis. The mechanism of action, toxicology, clinical efficacy, etc. of paclitaxel are reviewed in a number of articles, such as in the article by Rowinsky et al. in Taxol: A Novel Investigational Antimicrotubule Agent, J. Natl. Cancer Inst., 82: pp 1247-1259 (1990); and in "The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics" Pharmac, Ther., 52:35-84 (1991).
Since the discovery of its significant effectiveness in cancer treatment, many laboratories have launched programs to design paclitaxel analogues in search of better pharmacological profiles. Out of such programs, for example, was the discovery of Taxotere.RTM. of the formula ##STR3## See, Biologically Active Taxol Analogues with Deleted A-Ring Side Chain Substitutents and Variable C-2' Configurations, J. Med. Chem., 34, pp 1176-1184 (1991); Relationships between the Structure of Taxol Analogues and Their Antimitotic Activity, J. Med. Chem., 34, pp 992-998 (1991).
The present invention relates to structurally novel paclitaxel derivatives with antitumor activities.